A neuron, also known as a nerve cell, is one of the structural and functional units of the nervous system of an organism. Neurons can transmit messages to other cells via chemical and electrical signals. Neurons can vary in shape and size, and the diameters of the neurons may range from about 4 μm to about 100 μm. The structure of a neuron can be roughly divided into three parts: a cell body, dendrites, and an axon, wherein the dendrites can transmit signals into the cell body, and the axon can transmit signals out from the cell body.
Purkinje cells belong to γ-aminobutyric acid (GABA) neurons in the cerebellum that are responsible for transmitting nerve impulses. Purkinje cells have a morphology larger than other neurons and have more dendrites. The main functions of Purkinje cells are transmitting neural signals and regulating sodium-potassium ion channels. Purkinje cells play a role in the coordination of movement in a living body. The degeneration of Purkinje cells (e.g., cell death, reduction in the number of cells, cellular damage, or a decrease in the signal transmission function caused by the reduction of dendrites) may damage the signal transmission function of Purkinje cells. It has been known that the degeneration of Purkinje cells is relevant to neuronal diseases, such as Alzheimer's disease, Parkinson's disease, and spinal cerebellar atrophy, and is a process indicator of these diseases (see Schilling, K. et al., 1991, Electrical activity in cerebellar cultures determines Purkinje cell dendritic growth patterns. Neuron 7, 891-902, which is entirely incorporated hereinto by reference). Accordingly, the treatment effects of the neuronal diseases, such as Alzheimer's disease, Parkinson's disease, and spinal cerebellar atrophy can be provided if the degeneration of Purkinje cells can be inhibited.
Spinocerebellar atrophy is one of the most common ataxia related disease. Patients of spinocerebellar atrophy commonly suffer from cerebellar ataxia, which results in movement coordination disorders, muscle tension reduction, eye movement disorders, and speech disorders, etc. Spinocerebellar atrophy is primarily caused by genetic or gene mutations, which leads to the production of abnormal CAG repeat sequences in the exon of Atxin-3 (ATXN3) gene on a specific chromosome and thus the long chain glutamine will be generated in the translated proteins and result in cell apoptosis. ATXN3 is a deubiquitinating enzyme (DUB). In the ubiquitin-proteasome pathway, ATXN3 plays a role in preventing abnormal protein aggregation. Depending on where the CAG repeat sequence is located in a patient, spinocerebellar atrophy can be classified into various subtypes, such as type 1 (SCA1), type 2 (SCA2), type 3 (SCA3), type 6 (SCA6), type 7 (SCAT), and DRPLA. SCA3, also known as Machado-Joseph disease (MJD), is the most common subtype of spinocerebellar atrophy, characterized by an abnormal CAG repeat sequence present in exon 10 of chromosome 14q32.1
Currently, there are no effective treatments in the clinic for diseases caused by the degeneration of Purkinje cells. The patients can at best receive physical therapy and respiratory care to reduce the incidence of complications and slow the progression of the disease. Therefore, there is still a need for a medicament for treating and/or delaying diseases related to the degeneration of Purkinje cells.
The inventors of the present invention found that phthalide can treat and/or delay the degeneration of Purkinje cells, and thus, can be used to treat and/or delay the onset of spinocerebellar atrophy, Alzheimer's disease, and/or Parkinson's disease.